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Entinostat

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https://www.readbyqxmd.com/read/28522584/cooperative-targets-of-combined-mtor-hdac-inhibition-promote-myc-degradation
#1
John K Simmons, Aleksandra M Michalowski, Benjamin J Gamache, Wendy DuBois, Jyoti Patel, Ke Zhang, Joy Gary, Shuling Zhang, Snehal Gaikwad, Daniel Connors, Nicholas Watson, Elena Leon, Jin-Qiu Chen, W Michael Kuehl, Maxwell P Lee, Adriana Zingone, Ola Landgren, Peter Ordentlich, Jing Huang, Beverly A Mock
Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared to single agents.  In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared to single agents...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28511906/design-synthesis-and-anti-tumor-activity-study-of-novel-histone-deacetylase-inhibitors-containing-isatin-based-caps-and-o-phenylenediamine-based-zinc-binding-groups
#2
Shuai Gao, Jie Zang, Qianwen Gao, Xuewu Liang, Qinge Ding, Xiaoyang Li, Wenfang Xu, C James Chou, Yingjie Zhang
As a hot topic of epigenetic studies, histone deacetylases (HDACs) are related to lots of diseases, especially cancer. Further researches indicated that different HDAC isoforms played various roles in a wide range of tumor types. Herein a novel series of HDAC inhibitors with isatin-based caps and o-phenylenediamine-based zinc binding groups have been designed and synthesized through scaffold hopping strategy. Among these compounds, the most potent compound 9n exhibited similar if not better HDAC inhibition and antiproliferative activities against multiple tumor cell lines compared with the positive control entinostat (MS-275)...
March 19, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28498806/epigenetic-modifiers-upregulate-mhc-ii-and-impede-ovarian-cancer-tumor-growth
#3
Taylor B Turner, Selene Meza-Perez, Angelina Londoño, Ashwini Katre, Jacelyn E Peabody, Haller J Smith, Andres Forero, Lyse A Norian, J Michael Straughn, Donald J Buchsbaum, Troy D Randall, Rebecca C Arend
Expression of MHC class II pathway proteins in ovarian cancer correlates with prolonged survival. Murine and human ovarian cancer cells were treated with epigenetic modulators - histone deacetylase inhibitors and a DNA methyltransferase inhibitor. mRNA and protein expression of the MHC II pathway were evaluated by qPCR and flow cytometry. Treatment with entinostat and azacytidine of ID8 cells in vitro increased mRNA levels of Cd74, Ciita, and H2-Aa, H2-Eb1. MHC II and CD74 protein expression were increased after treatment with either agent...
April 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28465444/histone-deacetylase-inhibitor-enhances-the-efficacy-of-mek-inhibitor-through-noxa-mediated-mcl1-degradation-in-triple-negative-and-inflammatory-breast-cancer
#4
Angie M Torres-Adorno, Jangsoon Lee, Takahiro Kogawa, Peter Ordentlich, Debu Tripathy, Bora Lim, Naoto T Ueno
Purpose: Inflammatory breast cancer (IBC), diagnosed clinically, and triple-negative breast cancer (TNBC), diagnosed by molecular receptor status, are the two most aggressive forms of breast cancer, and both lack effective targeted therapies. We previously demonstrated involvement of histone deacetylase (HDAC) inhibitor entinostat in regulating apoptosis in IBC and TNBC cells; here, we aimed to identify novel combination therapy candidates. <p>Experimental Design: Potential therapeutic targets were identified by mRNA expression profiling of TNBC and IBC cells treated with entinostat...
May 2, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28447718/role-of-histone-deacetylase-expression-levels-and-activity-in-the-inflammatory-responses-of-patients-with-chronic-hepatitis-b
#5
Haiyue Zhang, Xun Li, Qian Zhang, Fan Yang, Xiaogang Chu, Di Zhang, Luwen Wang, Zuojiong Gong
Histone acetylation has been demonstrated to serve a pivotal role in numerous inflammatory diseases. The present study examined histone acetylation in patients with chronic hepatitis B (CHB) and CHB with liver failure by detecting histone deacetylase (HDAC) activity. Mice with acute liver failure (ALF) were treated with the HDAC inhibitor entinostat (MS275) and alterations in HDAC activity and pro‑inflammatory cytokine expression levels were detected. The effect of HDAC1 silencing on LPS-treated RAW264.7 murine macrophages was examined using specific small interfering RNA sequences, and the acetylation level of the non‑histone nuclear factor‑κB (NF‑κB) p65 subunit was additionally examined...
May 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28438947/treatment-with-entinostat-heals-experimental-cholera-by-affecting-physical-and-chemical-barrier-functions-of-intestinal-epithelia
#6
Protim Sarker, Atanu Banik, Roger Stromberg, Gudmundur H Gudmundsson, Rubhana Raqib, Birgitta Agerberth
We have previously shown that oral treatment of an experimental model of shigellosis with sodium butyrate or phenylbutyrate improves clinical outcome and induces the expression of the antimicrobial peptide CAP-18 in the large intestinal epithelia. In a subsequent study, we have found that Entinostat, an aroylated phenylenediamine compound has similar therapeutic potential against shigellosis. Here, we aim to evaluate Entinostat as a potential candidate for host-directed therapy against cholera in an experimental model...
April 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28421257/histone-deacetylase-inhibitors-reverse-age-related-increases-in-side-effects-of-haloperidol-in-mice
#7
Janitza L Montalvo-Ortiz, Daniel W Fisher, Guadalupe Rodríguez, Deyu Fang, John G Csernansky, Hongxin Dong
BACKGROUND: Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. METHODS: In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects...
April 18, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28340413/design-synthesis-and-biological-evaluation-of-novel-coumarin-based-benzamides-as-potent-histone-deacetylase-inhibitors-and-anticancer-agents
#8
Tooba Abdizadeh, Mohammad Reza Kalani, Khalil Abnous, Zahra Tayarani-Najaran, Bibi Zahra Khashyarmanesh, Rahman Abdizadeh, Razieh Ghodsi, Farzin Hadizadeh
Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. It has four classes (I-IV), among them especially class I isozyme are involved in promoting tumor cells proliferation, angiogenesis, differentiation, invasion and metastasis and also viable targets for cancer therapeutics. A novel series of coumarin-based benzamides was designed and synthesized as HDAC inhibitors. The cytotoxic activity of the synthesized compounds (8a-u) was evaluated against six human cancer cell lines including HCT116, A2780, MCF7, PC3, HL60 and A549 and a single normal cell line (Huvec)...
May 26, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28338101/the-histone-deacetylase-inhibitor-valproic-acid-inhibits-nkg2d-expression-in-natural-killer-cells-through-suppression-of-stat3-and-hdac3
#9
Lulu Ni, Lixin Wang, Chao Yao, Zhongya Ni, Fei Liu, Chenyuan Gong, Xiaowen Zhu, Xuewei Yan, Stephanie S Watowich, Dean A Lee, Shiguo Zhu
NKG2D is a major activating receptor of NK cells and plays a critical role in tumor immunosurveillance. NKG2D expression in NK cells is inhibited by the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and enhanced by the narrow-spectrum HDAC inhibitor entinostat. We previously demonstrated that entinostat enhanced NKG2D transcription by increasing acetylation of Histones H3 and H4. However, the mechanism by which VPA reduces NKG2D expression in NK cells is not known. We have also shown that NKG2D transcription is regulated by STAT3 phosphorylation...
March 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28326839/entinostat-a-promising-treatment-option-for-patients-with-advanced-breast-cancer
#10
Roisin M Connolly, Michelle A Rudek, Richard Piekarz
Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does not currently have regulatory approval for clinical use; however promising preclinical and clinical data exist in hormone-resistant breast cancer...
March 9, 2017: Future Oncology
https://www.readbyqxmd.com/read/28315487/xpln-is-modulated-by-hdac-inhibitors-and-negatively-regulates-sparc-expression-by-targeting-mtorc2-in-human-lung-fibroblasts
#11
Koichiro Kamio, Arata Azuma, Jiro Usuki, Kuniko Matsuda, Minoru Inomata, Nobuhiko Nishijima, Shioto Itakura, Hiroki Hayashi, Takeru Kashiwada, Nariaki Kokuho, Kenichiro Atsumi, Tomoyoshi Yamaguchi, Kazue Fujita, Yoshinobu Saito, Shinji Abe, Kaoru Kubota, Akihiko Gemma
Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extracellular matrix, whose expression is regulated by transforming growth factor (TGF)-β1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown...
June 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28186961/combination-epigenetic-therapy-in-metastatic-colorectal-cancer-mcrc-with-subcutaneous-5-azacitidine-and-entinostat-a-phase-2-consortium-stand-up-2-cancer-study
#12
Nilofer S Azad, Anthony El-Khoueiry, Jun Yin, Ann L Oberg, Patrick Flynn, Douglas Adkins, Anup Sharma, Daniel J Weisenberger, Thomas Brown, Prakriti Medvari, Peter A Jones, Hariharan Easwaran, Ihab Kamel, Nathan Bahary, George Kim, Joel Picus, Henry C Pitot, Charles Erlichman, Ross Donehower, Hui Shen, Peter W Laird, Richard Piekarz, Stephen Baylin, Nita Ahuja
PURPOSE: Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. EXPERIMENTAL DESIGN: We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28077797/repression-of-fyn-related-kinase-in-breast-cancer-cells-is-associated-with-promoter-site-specific-cpg-methylation
#13
Edward T Bagu, Sayem Miah, Chenlu Dai, Travis Spriggs, Yetunde Ogunbolude, Erika Beaton, Michelle Sanders, Raghuveera K Goel, Keith Bonham, Kiven E Lukong
The triple-negative breast cancer subtype is highly aggressive and has no defined therapeutic target. Fyn-related kinase (FRK) is a non-receptor tyrosine kinase, reported to be downregulated in breast cancer and gliomas, where it is suggested to have tumor suppressor activity. We examined the expression profile of FRK in a panel of 40 breast cancer cells representing all the major subtypes, as well as in 4 non-malignant mammary epithelial cell lines. We found that FRK expression was significantly repressed in a proportion of basal B breast cancer cell lines...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28052439/an-hdac-inhibitor-entinostat-ms-275-partially-prevents-delayed-cranial-suture-closure-in-heterozygous-runx2-null-mice
#14
Han-Sol Bae, Won-Joon Yoon, Young-Dan Cho, Rabia Islam, Hye-Rim Shin, Bong-Soo Kim, Jin-Muk Lim, Min-Seok Seo, Seo-Ae Cho, Kang-Young Choi, Seung-Hak Baek, Hong-Gee Kim, Kyung-Mi Woo, Jeong-Hwa Baek, Yun-Sil Lee, Hyun-Mo Ryoo
Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder caused by mutations in RUNX2, coding a key transcription factor of early osteogenesis. CCD patients suffer from developmental defects in cranial bones. Despite numerous investigations and clinical approaches, no therapeutic strategy has been suggested to prevent CCD. Here, we show that fetal administration of Entinostat/MS-275, a class I histone deacetylase (HDAC)-specific inhibitor, partially prevents delayed closure of cranial sutures in Runx2(+/-) mice strain of C57BL/6J by two mechanisms: 1) posttranslational acetylation of Runx2 protein, which stabilized the protein and activated its transcriptional activity; and 2) epigenetic regulation of Runx2 and other bone marker genes...
May 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28011471/histone-deacetylase-inhibitors-an-attractive-therapeutic-strategy-against-breast-cancer
#15
REVIEW
Christos Damaskos, Serena Valsami, Michael Kontos, Eleftherios Spartalis, Theodoros Kalampokas, Emmanouil Kalampokas, Antonios Athanasiou, Demetrios Moris, Afrodite Daskalopoulou, Spyridon Davakis, Gerasimos Tsourouflis, Konstantinos Kontzoglou, Despina Perrea, Nikolaos Nikiteas, Dimitrios Dimitroulis
With a lifetime risk estimated to be one in eight in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide. Patients are often treated with anti-estrogens, but it is common that some tumors develop resistance to therapy. The causation and progression of cancer is controlled by epigenetic processes, so there is an ongoing interest in research into mechanisms, genes and signaling pathways associating carcinogenesis with epigenetic modulation of gene expression. Given the fact that histone deacetylases (HDACs) have a great impact on chromatin remodeling and epigenetics, their inhibitors have become a very interesting field of research...
2017: Anticancer Research
https://www.readbyqxmd.com/read/27999738/the-interplay-of-epigenetic-therapy-and-immunity-in-locally-recurrent-or-metastatic-estrogen-receptor-positive-breast-cancer-correlative-analysis-of-encore-301-a-randomized-placebo-controlled-phase-ii-trial-of-exemestane-with-or-without-entinostat
#16
Yusuke Tomita, Min-Jung Lee, Sunmin Lee, Saori Tomita, Saranya Chumsri, Scott Cruickshank, Peter Ordentlich, Jane B Trepel
Entinostat, a class I-selective histone deacetylase inhibitor, has shown promising activity in ENCORE 301, a randomized, placebo-controlled, phase II trial of exemestane with or without entinostat in women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor. ENCORE 301 showed an 8.3-mo improvement in median overall survival among patients who received entinostat. We investigated the impact of entinostat on immune subsets with CD40, HLA-DR, and immune checkpoint receptor expression analyses in 34 patient blood samples from ENCORE 301...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27979916/combination-epigenetic-therapy-in-advanced-breast-cancer-with-5-azacitidine-and-entinostat-a-phase-ii-national-cancer-institute-stand-up-to-cancer-study
#17
Roisin M Connolly, Huili Li, Rachel C Jankowitz, Zhe Zhang, Michelle A Rudek, Stacie C Jeter, Shannon A Slater, Penny Powers, Antonio C Wolff, John H Fetting, Adam Brufsky, Richard Piekarz, Nita Ahuja, Peter W Laird, Hui Shen, Daniel J Weisenberger, Leslie Cope, James G Herman, George Somlo, Agustin A Garcia, Peter A Jones, Stephen B Baylin, Nancy E Davidson, Cynthia A Zahnow, Vered Stearns
Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC).Experimental Design: Patients received 5-azacitidine 40 mg/m(2) (days 1-5, 8-10) and entinostat 7 mg (days 3, 10) on a 28-day cycle...
June 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27892955/erratum-the-histone-deacetylase-inhibiting-drug-entinostat-induces-lipid-accumulation-in-differentiated-heparg-cells
#18
Abigail D G Nunn, Tullio Scopigno, Natalia Pediconi, Massimo Levrero, Henning Hagman, Juris Kiskis, Annika Enejder
No abstract text is available yet for this article.
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27797970/molecular-pathways-maintaining-mapk-inhibitor-sensitivity-by-targeting-nonmutational-tolerance
#19
Michael P Smith, Claudia Wellbrock
Targeting hyperactive MAPK signaling has proven to be an effective treatment for a variety of different cancers. Responses to the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitors trametinib and cobimetinib are, however, transient, and complete remission is rarely observed; rather, outgrowth of resistant clones within progressed tumors appears inevitable. These resistant tumors display great heterogeneity, which poses a major challenge to any salvage therapy. Recent focus has, therefore, been on the early dynamics of inhibitor response during tumor regression...
December 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27792246/inhibition-of-histone-deacetylases-in-melanoma-a-perspective-from-bench-to-bedside
#20
REVIEW
Eva Hornig, Markus V Heppt, Saskia A Graf, Thomas Ruzicka, Carola Berking
Histone deacetylases (HDACs) are critically involved in epigenetic gene regulation through alterations of the chromatin status of DNA. Aberrant expression, dysregulation of their enzymatic activity or imbalances between HDACs and histone acetyltransferases are likely involved in the development and progression of cancer. Pharmacologic inhibition of HDACs shows potent antitumor activity in a panel of malignancies such as colon or gastric cancer and multiple myeloma. In this review, we summarize the current knowledge of HDACs in melanoma and evaluate the application of HDAC inhibition from an experimental and clinical perspective...
November 2016: Experimental Dermatology
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